Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking

A new method for cysteine–lysine cross-linking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an <i>O</i>-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a cross-link. The linkage so formed is stable toward acid, base, oxygen, and external thiol nucleophiles. This method was applied to cross-link cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular cross-linking between a peptide and a protein based on the p53-MDM2 interaction. These studies demonstrate the potential for palladium-mediated methods to serve as a platform for the development of future cross-linking techniques for peptides and proteins with natural amino acid residues

Additional file 1 of Comprehensive analysis and validation of SNX7 as a novel biomarker for the diagnosis, prognosis, and prediction of chemotherapy and immunotherapy response in hepatocellular carcinoma

Additional file 1

Salt Effect Accelerates Site-Selective Cysteine Bioconjugation

Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the <i>rate constant over 4 orders of magnitude</i> for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π-clamp) and a perfluoroaryl electrophile. Biocompatible ammonium sulfate significantly enhances the reaction rate without influencing the site-specificity of π-clamp mediated arylation, enabling the fast synthesis of two site-specific antibody–drug conjugates that selectively kill HER2-positive breast cancer cells. Computational and structure–reactivity studies indicate that salts may tune the reaction rate through modulating the interactions between the π-clamp hydrophobic side chains and the electrophile. On the basis of this understanding, the salt effect is extended to other bioconjugation chemistry, and a new regioselective alkylation reaction at π-clamp cysteine is developed

Photoredox C–F Quaternary Annulation Catalyzed by a Strongly Reducing Iridium Species

We report a <i>fac</i>–Ir­(ppy)₃*–Ir^II–Ir^III photocatalytic cycle involving <i>t</i>-BuOK as the terminal reductant in a visible-light-induced sp² C–F quaternary annulation reaction that proceeds in yields up to 98%. Because of the high activity of the Ir^II(ppy)₃ catalyst, even at a loading of 50 ppm, the annulation reaction was able to compete with an uncatalyzed nucleophilic aromatic substitution reaction. The annulation reaction was stereoconvergent, and an annulated product was synthesized with complete retention of enantiomeric excess

Designing Well-Structured Cyclic Pentapeptides Based on Sequence–Structure Relationships

Cyclic peptides are a promising class of molecules for unique applications. Unfortunately, cyclic peptide design is severely limited by the difficulty in predicting the conformations they will adopt in solution. In this work, we use explicit-solvent molecular dynamics simulations to design well-structured cyclic peptides by studying their sequence–structure relationships. Critical to our approach is an enhanced sampling method that exploits the essential transitional motions of cyclic peptides to efficiently sample their conformational space. We simulated a range of cyclic pentapeptides from all-glycine to a library of cyclo-(X₁X₂AAA) peptides to map their conformational space and determine cooperative effects of neighboring residues. By combining the results from all cyclo-(X₁X₂AAA) peptides, we developed a scoring function to predict the structural preferences for X₁–X₂ residues within cyclic pentapeptides. Using this scoring function, we designed a cyclic pentapeptide, cyclo-(GNSRV), predicted to be well structured in aqueous solution. Subsequent circular dichroism and NMR spectroscopy revealed that this cyclic pentapeptide is indeed well structured in water, with a nuclear Overhauser effect and <i>J</i>-coupling values consistent with the predicted structure

Rational Design of α‑Fe₂O₃/Reduced Graphene Oxide Composites: Rapid Detection and Effective Removal of Organic Pollutants

α-Fe₂O₃/reduced graphene oxide (α-Fe₂O₃/rGO) composites are rationally designed and prepared to integrate organic pollutants detection and their photocatalytic degradation. Specifically, the composites are used as the substrate for surface-enhanced Raman scattering (SERS) to detect rhodamine 6G (R6G). Repeatable strong SERS signals could be obtained with R6G concentration as low as 10^–5 M. In addition, the substrate exhibits self-cleaning properties under solar irradiation. Compared with pure α-Fe₂O₃ and α-Fe₂O₃/rGO mechanical mixtures, the α-Fe₂O₃/rGO composites show much higher photocatalytic activity and much greater Raman enhancement factor. After 10 cycling measurements, the photodegradation rate of R6G could be maintained at 90.5%, indicating high stability of the photocatalyst. This study suggests that the α-Fe₂O₃/rGO composites would serve both as recyclable SERS substrate and as excellent visible light photocatalyst

Solid Electrolyte Interphase Structure Regulated by Functional Electrolyte Additive for Enhancing Li Metal Anode Performance

Lithium (Li) metal anodes have become an important component of the next generation of high energy density batteries. However, the Li metal anode still has problems such as Li dendrite growth and unstable solid electrolyte interface layer. Herein, we present a functional electrolyte additive (PANHF) successfully synthesized from acrylonitrile and hexafluorobutyl methacrylate via a polymerization reaction. With extensive analytical characterization, it is found that the PANHF can improve the reversibility and Coulombic efficiency of the Li deposition/dissolution reaction and prevent the growth of Li dendrites by forming a solid electrolyte interphase rich in organic matter on the outer layer and LiF on the inner layer. The results show that the cycling performance of the Li/Li cell was greatly improved in the electrolyte containing 0.5 wt % PANHF. Specifically, the cycling stability of more than 700 cycles was achieved at a current density of 1.0 mA cm–2. Moreover, the Li/NCM811 cell with 0.5 wt % PANHF has a higher capacity of 137.7 mA h g–1 at 1.0 C and a capacity retention of 83.41% after 200 cycles. This work highlights the importance of protecting the Li metal anode with functional bipolymer additives for next-generation Li metal batteries

Bifunctional Unnatural Sialic Acids for Dual Metabolic Labeling of Cell-Surface Sialylated Glycans

Sialic acid analogues containing a unique chemical functionality or chemical reporter have been metabolically incorporated into sialylated glycans. This process, termed metabolic glycan labeling, has emerged as a powerful tool for studying sialylation as well as other types of glycosylation. Currently, this technique can install only a single functionality. Here we describe a strategy for dual labeling of sialylated glycans using a new class of bifunctional sialic acid analogues containing two distinct chemical reporters at the <i>N</i>-acyl and C9 positions. These bifunctional unnatural sialic acids were metabolically incorporated into cellular glycans, where the two chemical reporters exerted their distinct functions. This approach expands the capability of metabolic glycan labeling to probe sialylation and glycan–protein interactions

Tuning Electrochemical Properties of Li-Rich Layered Oxide Cathodes by Adjusting Co/Ni Ratios and Mechanism Investigation Using in situ X‑ray Diffraction and Online Continuous Flow Differential Electrochemical Mass Spectrometry

Owing to high specific capacity of ∼250 mA h g^–1, lithium-rich layered oxide cathode materials (Li_1+<i>x</i>Ni_<i>y</i>Co_<i>z</i>Mn_{(3–<i>x</i>–2<i>y</i>–3<i>z</i>)/4}O₂) have been considered as one of the most promising candidates for the next-generation cathode materials of lithium ion batteries. However, the commercialization of this kind of cathode materials seriously restricted by voltage decay upon cycling though Li-rich materials with high cobalt content have been widely studied and show good capacity. This research successfully suppresses voltage decay upon cycling while maintaining high specific capacity with low Co/Ni ratio in Li-rich cathode materials. Online continuous flow differential electrochemical mass spectrometry (OEMS) and in situ X-ray diffraction (XRD) techniques have been applied to investigate the structure transformation of Li-rich layered oxide materials during charge–discharge process. The results of OEMS revealed that low Co/Ni ratio lithium-rich layered oxide cathode materials released no lattice oxygen at the first charge process, which will lead to the suppression of the voltage decay upon cycling. The in situ XRD results displayed the structure transition of lithium-rich layered oxide cathode materials during the charge–discharge process. The Li_1.13Ni_0.275Mn_0.580O₂ cathode material exhibited a high initial medium discharge voltage of 3.710 and a 3.586 V medium discharge voltage with the lower voltage decay of 0.124 V after 100 cycles

The Discovery of <i>N</i>‑((2<i>H</i>‑Tetrazol-5-yl)methyl)-4-((<i>R</i>)‑1-((5<i>r</i>,8<i>R</i>)‑8‑(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): A Potent and Selective Glucagon Receptor Antagonist

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound <b>1</b>, <i>N</i>-((2<i>H</i>-tetrazol-5-yl)­methyl)-4-((<i>R</i>)-1-((5<i>r</i>,8<i>R</i>)-8-(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro­[4.5]­dec-3-en-1-yl)-4,4-dimethylpentyl)­benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of <b>1</b> lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound <b>1</b>, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice